Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice

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Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice Gerard E. Kaiko, PhD, BBiomedSc (Hons), Zhixuan Loh, BSc (Hons), Kirsten Spann, PhD, BSc (Hons), Jason P. Lynch, BSc (Hons), Amit Lalwani, BSc (Hons), Zhenglong Zheng, BSc (Hons), Sophia Davidson, BSc (Hons), Satoshi Uematsu, MD, PhD, Shizuo Akira, MD, PhD, John Hayball, PhD, Kerrilyn R. Diener, PhD, Katherine J. Baines, PhD, BBiomedSci (Hons), Jodie L. Simpson, PhD, BSc (Hons), Paul S. Foster, PhD, BSc (Hons), Simon Phipps, PhD, BSc (Hons) Journal of Allergy and Clinical Immunology Volume 131, Issue 5, Pages 1331-1339.e10 (May 2013) DOI: 10.1016/j.jaci.2013.02.041 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Reduced viral clearance and enhanced pathology occurs in the absence of TLR7. A, Survival. B, Viral load in the lungs determined by means of quantitative PCR. HPRT, Hypoxanthine-guanine phosphoribosyltransferase. C, Micrographs (×400 magnification) of lung sections probed with anti-PVM (brown) and quantification of AEC expression (7 dpi). D, Micrographs (×1000 magnification) of epithelial shedding and quantification of denudation at 7 dpi. E, Micrographs (×1000 magnification) of lung sections probed with anti–IL-1β (red) and quantification of AEC expression at 4 dpi. **P < .01 and ***P < .001 compared with PVM-infected TLR7+/+ mice. Data are presented as means ± SEMs for one experiment representative of 2 experiments, each with 4 to 7 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Pneumoviral infection in the absence of TLR7 promotes TH2 immunity. A, Type 2 ILCs in the lungs. B, Amphiregulin protein in lung homogenates. C, AEC hyperplasia at 10 dpi. D, IL-13 gene and protein expression in the lung and BAL fluid. E, IL-25 and IL-33 protein expression in BAL fluid. *P < .05, **P < .01, and ***P < .001 compared with PVM-infected samples. Data are presented as means ± SEMs of one experiment representative of 2 experiments, each with 5 to 7 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Reinfection with virus in later life leads to TH2 responses and airways hyperreactivity in the absence of TLR7. A, Study design. B, Serum PVM-specific IgG at 6 days after secondary infection. C, Viral load in the lungs. The dotted line indicates limit of detection. D, Gene expression in the lung. E, Cytokine release from DLN cells. F, Tissue eosinophils. BM, Basement membrane. G and H, Airways resistance and airways compliance. I, Number of airways with a contiguous surrounding layer of smooth muscle (SM) sheath. *P < .05, **P < .01, and ***P < .001 compared with PVM-infected TLR7+/+ mice. Data are presented as means ± SEMs for one experiment representative of 2 experiments, each with 4 to 7 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Mast cell numbers and IgE levels increase with each subsequent viral infection. Measurements were conducted 7, 6, and 6 days after the first, second, and third PVM infection, respectively. A, Concentration of serum total IgE. B, Toluidine blue–positive mast cells. BM, Basement membrane. **P < .01 and ***P < .001 compared with PVM-infected TLR7+/+ mice. Data are presented as means ± SEMs for one experiment representative of 2 experiments, each with 4 to 7 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Virus-induced airway inflammation and airway hyperreactivity is dependent on memory CD4 T cells. A, Gene expression in the lung. B, Cytokine release by DLN cells. C and D, Airways resistance and airways compliance. MCh, Methacholine. Vehicle represents the PVM vehicle control/noninfected TLR7−/− mice. *P < .05 and **P < .01 compared with isotype-treated mice. Data are presented as means ± SEMs for 4 to 7 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Pneumoviral infection in early life in the absence of TLR7 increases sensitization to cockroach antigen (CRAg) and promotes TH2 lung inflammation. A, Study design. B, IL-5 in BAL fluid. C, Tissue eosinophils. BM, Basement membrane. D, Mucus-secreting cells. E, Toluidine blue–positive mast cells. *P < .05, **P < .01, and ***P < .001 compared with PVM + CRAg TLR7+/+ mice or CRAg TLR7−/− mice, as indicated. Data are presented as means ± SEMs for 4 to 6 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 The absence of TLR7 attenuates Pneumovirus-induced interferon responses and increases inflammasome activation. A, Hematoxylin-stained lung sections demonstrate parenchymal consolidation. B, IFN-α and IFN-β gene and IFN-α protein expression in BAL fluid. C, IFN-γ lung gene expression. D, IL-1β protein in lung homogenate. E, Caspase-1 activity in lung homogenate. F, IL-1β in the BAL fluid. *P < .05, **P < .01, and ***P < .001 compared with PVM-infected TLR7+/+ mice or **P < .01 compared with vehicle control mice (caspase-1 activity). Data are presented as means ± SEMs for one experiment representative of 2 experiments, each with 4 to 7 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Pneumoviral infection in the absence of TLR7 promotes TH2 responses. A, IL-4 lung gene expression. B, Cytokine release from DLNs. C, Eotaxin-2 protein in lung homogenates at 7 dpi. D, Tissue eosinophils. BM, Basement membrane. E, TSLP, IL-25, and IL-33 gene expression in the lung. F, CD11c+CD11b+ MHC class II–positive conventional DCs (cDCs) in the lungs. *P < .05, **P < .01, and ***P < .001 compared with PVM-infected TLR7+/+ mice or vehicle control TLR7+/+ mice. Data are presented as means ± SEMs of one experiment representative of 2 experiments, each with 5 to 7 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Pneumoviral infection induces profuse airway mucus production independent of TLR7. A, Lung histologic sections were stained for hematoxylin and periodic acid–Schiff and assessed for mucus-secreting cells. B, Lung histologic sections were stained for α-smooth muscle actin and assessed for smooth muscle banding. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Reinfection of TLR7−/− mice on a C57BL/6 background is associated with TH2 lung inflammation. A, Eotaxin-2 protein in lung homogenates. B, Airway eosinophils in BAL fluid. C, IL-13 protein in BAL fluid. D, IL-13 release by DLN cells. *P < .05 and ***P < .001 compared with PVM-infected TLR7+/+ mice. Data are presented as means ± SEMs, with 4 to 7 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Mast cells accumulate in the airway submucosa of TLR7−/− mice after successive pneumoviral infections. Micrographs at ×400 and ×1000 magnification show mast cells (deep blue) around the airways of TLR7−/− mice. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Tertiary infection in the absence of TLR7 leads to exacerbation of TH2 responses and airways hyperreactivity. A, Gene expression in the lung. B, Cytokine release from DLN cells. C, Tissue eosinophils. BM, Basement membrane. D and E, Airways resistance and airways compliance. F, The number of airways with a contiguous surrounding layer of smooth muscle (SM) sheath. *P < .05 and **P < .01 compared with PVM-infected TLR7+/+ mice. Data are presented as means ± SEMs for one experiment representative of 2 experiments, each with 4 to 7 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Study design and confirmation of depletion of CD4+ T cells. Neonatal (7-day-old) mice were inoculated with PVM at day 0 and then treated with an anti-CD4 depleting antibody (GK1.5) at days 21, 23, and 25. At day 42, mice were reinoculated with PVM. Fluorescence-activated cell sorting histograms demonstrate the percentage of CD4 T cells (numbers in top right-hand quadrant) in the lungs and lymph nodes before depletion, during depletion, and at day 42 (2.5 weeks after depletion). Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Pneumoviral infection in early life in the absence of TLR7 increases TH2 gene expression in response to inhaled cockroach antigen (CRAg). Gene expression in the lung was analyzed for IFN-γ (A), IL-17A (B), IL-5 (C), eotaxin-2 (D), and IL-13 (E). *P < .05 and ***P < .001 compared with PVM + CRAg TLR7+/+ mice or CRAg TLR7−/− mice, as indicated. Data are presented as means ± SEMs for 4 to 6 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1331-1339.e10DOI: (10.1016/j.jaci.2013.02.041) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions